The starting materials for the methods of the present invention are linear diamino diols. These compounds include nonpeptide C-2 symmetric and pseudosymmetric compounds which have biological activity as human immunodeficiency virus (HIV) protease inhibitors. Numerous methods for their preparation are found in the literature. The N,N'-disubstituted cyclic urea products of the methods of the present invention have also exhibited biological activity as human immunodeficiency virus (HIV) protease inhibitors for the treatment of HIV infection.
Linear diaminodiols and methods for their preparation are found in the literature, for example in the following references: Kempf et al., J. Org. Chem. 57, 5692-5700 (1992); Livermore et al., J. Med. Chem. 36, 3784-3794 (1993); Lam et al., Science 263, 380-384 (1994); Dreyer et al., Biochemistry 32, 937-47 (1993); Sowin et al. WO 93/23361; Jadhav et al., Bioorganic & Med. Chem. Lett. 2, 353-356 (1992); Jadhav et al., U.S. Pat. No. 5,294,720 (issued Mar. 15, 1994); Dreyer et al., Biochemistry 32(3), 937-47 (1993); Canadian Patent Application 2,026,832 (German Patent Application DE 4030350); European Patent Application No. WO 92/00948; U.S. Pat. No. 4,837,204; and European Patent Application Publication Number 486,948.
Acetonide has been used to protect the diol function in the preparation of linear HIV protease inhibitors (Baker et al., J. Org. Chem. 58, 3277-3284 (1993); Baker et al., Tetrahedron Lett. 33, 1581-1584 (1992)).
Lam et al., PCT International Publication Number WO 93/07,128, EP 402646 A1, and copending commonly assigned U.S. patent application Ser. No. 08/197,630, filed Feb. 16, 1994, disclose cyclic carbonyl compounds and derivatives thereof which are useful as HIV protease inhibitors for the treatment of HIV infection. Such cyclic compounds, which may be made using the processes of the present invention, are non-peptidic, low molecular weight, orally bioavailable compounds useful as inhibitors of HIV protease and for the treatment of HIV infection.
Copending commonly assigned U.S. patent application Ser. No. 08/268,609, filed Jun. 30, 1994, discloses a process for the preparation of nitrogen-unsubstituted linear diaminodiols having an acetonide protecting group for the diol as shown in Scheme 1, and the cyclization of the nitrogen-unsubstituted acetonide protected linear diamino diol (V) to form a cyclic urea product compound. ##STR2##
Copending commonly assigned U.S. patent application Ser. No. 08/269,320, filed Jun. 30, 1994, discloses a process for the preparation of nitrogen-unsubstituted dihydroxy cyclic ureas having an acetonide protecting group for the diol as shown below in Scheme 2. The cyclization to the cyclic urea takes place on the diamino diol (VI) in which nitrogen is unprotected and the hydroxyls bear an acyclic protecting group. The diol protecting group had to be changed midway through the synthesis in order to optimize the cyclization and alkylation yields. ##STR3##
Copending commonly assigned U.S. patent application Ser. No. 08/268,702 filed Jun. 30, 1994, discloses a process for the preparation of nitrogen-unsubstituted dihydroxy cyclic ureas having a trioxepane protecting group for the diol as shown in Scheme 3. In this case the cyclization to the cyclic urea takes place on the nitrogen-unsubstituted trioxepane protected diaminodiol (IV). ##STR4##
Copending commonly assigned U.S. patent application Ser. No. 08/230,562, filed Apr. 20, 1994, discloses a process for the preparation of symmetrically or unsymmetrically nitrogen-disubstituted or nitrogen-monosubstituted cyclic ureas having a broad range of hydroxy protecting groups for the diol as shown below in Scheme 4. In this process, chromatographic separation of the unsubstituted and monosubstituted cyclic urea is required. Under the conditions disclosed in this reference, cyclization of the nitrogen-disubstituted hydroxyl protected diaminodiol with 1,1'-carbonyldiimidazole does not take place. ##STR5##
Copending commonly assigned U.S. patent application Ser. No. 08/197,630, filed Feb. 16, 1994, discloses a process for the preparation of symmetrically or unsymmetrically nitrogen-disubstituted or nitrogen-monosubstituted cyclic ureas having various hydroxy protecting groups, via cyclization of an un- (R.sup.22 and R.sup.23 are H), mono- (one of R.sup.22 and R.sup.23 are H and the other is nonhydrogen) or disubstituted (both R.sup.22 and R.sup.23 are not hydrogen) linear diamine to the respective cyclic urea as shown in Scheme 5. ##STR6## Also disclosed in this reference is the cyclization of a nitrogen-unsubstituted acetonide protected diaminodiol with CDI. The cyclization of a nitrogen-unsubstituted bis-Mem protected diaminodiol was shown to occur in high yield. The cyclization of a bis-Mem protected bis-monophenylhydrazinodiol (I) with phosgene to the corresponding cyclic urea (II),as shown below in Scheme is disclosed in this reference. ##STR7## The use of acyclic diol protecting groups allowed for high cyclization yields but produced intermediates which were undesirable oils. These intermediates also lead to lower yields in subsequent steps of the process.
Despite the various methods for their preparation, there still exists a need for more efficient and cost-effective methods for the preparation of such cyclic urea HIV protease inhibitor compounds in high yields from readily available starting materials. The present invention provides improved processes for the synthesis of such cyclic urea HIV protease inhibitor compounds and processes for the synthesis of intermediates for the synthesis of such cyclic urea HIV protease inhibitor compounds.
The present invention comprises a process which allows the entire synthetic sequence leading to the desired HIV protease inhibitors to be carried out using the inexpensive acetonide or oxydimethylene-1,3-diyl protecting groups. The present invention comprises an initial reductive alkylation of the diamine affording a crystalline intermediate in high yield. This intermediate compound undergoes cyclization with phosgene in high yield to produce another crystalline intermediate, providing an optimal process. Advantages of the present invention include: a) reduction in the number of chemical steps; b) increase in overall yield; and c) formation of crystalline intermediates.